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Abdominal pain represents 5% to 7% of all emergency department presentations. Many patients require imaging for diagnosis, and choosing the appropriate imaging modality is a crucial decision point. Modern medicine offers a fantastic array of options including abdominal radiograph, computed tomography, MRI, and ultrasonography, but the plethora of alternatives can be paralyzing. This article introduces the commonly available modalities, discusses the advantages and disadvantages, and presents current recommendations for commonly diagnosed conditions.

OBJECTIVE The objective of this study was to compare results of using web-based and mail (postal) Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) data collection protocols. RESEARCH DESIGN Patients who had been hospitalized in a New England Hospital were surveyed about their hospital experience. Patients who provided email addresses were randomized to 1 of 3 data collection protocols: web-alone, web with postal mail follow-up, and postal mail only. Those who did not provide email addresses were surveyed using postal mail only. Analyses compared response rates, respondent characteristics, and patient-reported experiences. SUBJECTS For an 8-week period, patients were discharged from the study hospital to home. MEASURES Measures included response rates, characteristics of respondents, 6 composite measures of their patient experiences, and 2 ratings of the hospital. RESULTS Response rates were significantly lower for the web-only protocol than the mail or combined protocols, and those who had not provided email addresses had lower response rates. Those over 65 were more likely than others to respond to all protocols, especially for the mail-only protocols. Respondents without email addresses were older, less educated, and reported worse health than those who provided email addresses. After adjusting for respondent differences, those in the combined protocol differed significantly from the mail (postal) only respondents on 2 measures of patient experience; those in the web-only protocol differed on one. Those not providing an email address differed from those who did on one measure. CONCLUSION If web-based protocols are used for HCAHPS surveys, adjustments for a mode of data collection are needed to make results comparable.

Sport specialization is becoming increasingly common among youth and adolescent athletes in the United States and many have raised concern about this trend. Although research on sport specialization has grown significantly, numerous pressing questions remain pertaining to short- and long-term effects of specialization on the health and well-being of youth, including the increased risk of overuse injury and burnout. Many current elite athletes did not specialize at an early age. Methodological and study design limitations impact the quality of current literature, and researchers need to prioritize pressing research questions to promote safe and healthy youth sport participation. The American Medical Society for Sports Medicine hosted a Youth Early Sport Specialization Summit in April 2019 with the goal of synthesizing and reviewing current scientific knowledge and developing a research agenda to guide future research in the field based on the identified gaps in knowledge. This statement provides a broad summary of the existing literature, gaps and limitations in current evidence, and identifies key research priorities to help guide researchers conducting research on youth sport specialization. Our goals are to help improve the quality and relevance of research on youth sport specialization and to ultimately assure that opportunities for healthy and safe sport participation continue for all youth.

Objectives To compare the efficacy and safety of algenpantucel-L (HAPa; IND# 12311) immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). Summary background data To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. Methods A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. Results Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (IQR) overall survival was 14.9 (12.2-17.8) months in the standard group (N=158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) (hazard ratio [HR] 1.02, 95% CI 0.66-1.58; P = 0.98). Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% CI 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). Conclusions Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. Trial registration ClinicalTrials.gov Identifier: NCT01836432.

Back pain has long been considered an uncommon complaint in the pediatric population. When present, teaching had been that pediatric back pain almost always has a diagnosable cause, many of which are progressive and potentially debilitating. Recent evidence has suggested that pediatric back pain is not only more common than once thought but also, within certain populations, benign and idiopathic. This, in turn, places an increasing amount of pressure on pediatricians to accurately assess and manage their patients presenting with complaints of back pain. The aim of this article is to serve as a review of the current literature on pediatric back pain. The article reviews the epidemiology, basic anatomy, and important elements of a history and examination, which should be considered when a child presents complaining of back pain. Last, a common differential diagnosis with evaluation and management is also given to help guide pediatricians through their medical decision making.

Background: Concerns for youth sports in the United States often focus on early sport specialization, overemphasis on competition, injuries, and burnout. Little research has addressed relationships among the preceding and other concerns, including time away from organized sport, sleep, and perceptions of physical and psychological well-being. Hypothesis: There is an association between reported competitive gameplay volume and specialization, injury, and fatigue among elite youth basketball players. Study Design: Cross-sectional study; convenience sample. Level of Evidence: Level 4. Methods: An anonymous questionnaire was administered to a convenience sample of youth basketball players between 13 and 18 years of age from across the United States. Participants were queried about multiple factors, including the extent of their participation in organized basketball and other sports, time away from organized basketball, injury, sleep, and feelings of exhaustion related to basketball participation. Results: A total of 772 participants (145 girls, 627 boys) completed a survey. All participants played for a select or elite club basketball team and/or a high school basketball team. Overall, 49% played more than 50 games within the past year. A total of 73% were specialized in basketball, 58% prior to age 14 years, and 35% prior to age 11 years. In all, 70% reported less than 1 month away from organized basketball within the past year, and 28% reported no time away. A total of 54% reported sleeping less than the recommended 8 hours each night during the school year. Within the prior year, 55% reported feeling physically exhausted and 45% reported feeling mentally exhausted from basketball. Regression analysis did not find any significant relationships between early specialization prior to age 14 years and basketball-related injury or feelings of mental or physical exhaustion. Conclusion: In this select group of youth basketball players, the majority specialized in basketball prior to age 14 years and reported a large number of competitive events with little time away from organized basketball. Clinical Relevance: The results from a sample of highly competitive youth basketball players indicate issues that warrant further attention and research regarding the potential impact of specialization, frequent competitions, lack of time away from organized sport, and perceptions of well-being in young athletes.

Introduction Wearable biosensors have the potential to monitor physiological change associated with opioid overdose among people who use drugs. Methods We enrolled 16 individuals who reported ≥4 daily opioid use events within the previous 30 day. Each was assigned a wearable biosensor that measured respiratory rate (RR) and actigraphy every 15 seconds for 5 days and also completed a daily interview assessing drug use. We describe the volume of RR data collected, how it varied by participant characteristics and drug use over time using repeated measures one-way ANOVA, episodes of acute respiratory depression (≤5 breaths/minute), and self-reported overdose experiences. Results We captured 1626.4 hours of RR data, an average of 21.7 daily hours/participant over follow-up. Individuals with longer injection careers and those engaging in polydrug use captured significantly fewer total hours of respiratory data over follow-up compared to those with shorter injections careers (94.7 vs. 119.9 hours, p = 0.04) and injecting fentanyl exclusively (98.7 vs. 119.5 hours, p = 0.008), respectively. There were 385 drug use events reported over follow-up. There were no episodes of acute respiratory depression which corresponded with participant reports of overdose experiences. Discussion Our preliminary findings suggest that using a wearable biosensor to monitor physiological changes associated with opioid use was feasible. However, more sensitive biosensors that facilitate triangulation of multiple physiological data points and larger studies of longer duration are needed.

Graphical abstract Targeted drug delivery and nanomedicine hold the potential promise of delivering drugs solely to target organs or cell types, thus decreasing off-target side effects and improving efficacy. However, nano-scale drug carriers face several barriers to this goal, with one of the most formidable being the complement cascade. Complement proteins, especially C3, opsonize not just the microbes they evolved to contain, but also nanocarriers. This results in multiple problems, including marking the nanocarriers for clearance by leukocytes, likely fouling of the targeting moieties on nanocarriers, and release of toxins which produce deleterious local and systemic effects. Here, we review how complement achieves its blockade of nanomedicine, which nanocarrier materials properties best avoid complement, and current and future strategies to control complement to unleash nanomedicine’s potential.

New advances in intra-arterial (IA) catheters offer clinically proven local interventions in the brain. Here we tested the effect of combining local IA delivery and vascular immunotargeting. Microinjection of tumor necrosis factor alpha (TNFα) in the brain parenchyma causes cerebral overexpression of Inter-Cellular Adhesion Molecule-1 (ICAM-1) in mice. Systemic intravenous injection of ICAM-1 antibody (anti-ICAM-1) and anti-ICAM-1/liposomes provided nearly an order of magnitude higher uptake in the inflamed vs normal brain (from ~0.1 to 0.8%ID/g for liposomes). Local injection of anti-ICAM-1 and anti-ICAM-1/liposomes via carotid artery catheter provided an additional respective 2-fold and 5-fold elevation of uptake in the inflamed brain vs levels attained by IV injection. The uptake in the inflamed brain of respective untargeted IgG counterparts was markedly lower (e.g., uptake of anti-ICAM-1/liposomes was 100-fold higher vs IgG/liposomes). These data affirm the specificity of the combined effect of the first pass and immunotargeting. Intravital real-time microscopy via cranial window revealed that anti-ICAM-1/liposomes, but not IgG/liposomes bind to the lumen of blood vessels in the inflamed brain within minutes after injection. This straightforward framework provides the basis for translational efforts towards local vascular drug targeting to the brain.

Background The incidence of opioid-related overdose deaths has been rising for 30 years and has been further exacerbated amidst the COVID-19 pandemic. Naloxone can reverse opioid overdose, lower death rates, and enable a transition to medication for opioid use disorder. Though current formulations for community use of naloxone have been shown to be safe and effective public health interventions, they rely on bystander presence. We sought to understand the preferences and minimum necessary conditions for wearing a device capable of sensing and reversing opioid overdose among people who regularly use opioids. Methods We conducted a combined cross-sectional survey and semi-structured interview at a respite center, shelter, and syringe exchange drop-in program in Philadelphia, Pennsylvania, USA, during the COVID-19 pandemic in August and September 2020. The primary aim was to explore the proportion of participants who would use a wearable device to detect and reverse overdose. Preferences regarding designs and functionalities were collected via a questionnaire with items having Likert-based response options and a semi-structured interview intended to elicit feedback on prototype designs. Independent variables included demographics, opioid use habits, and previous experience with overdose. Results A total of 97 adults with an opioid use history of at least 3 months were interviewed. A majority of survey participants (76%) reported a willingness to use a device capable of detecting an overdose and automatically administering a reversal agent upon initial survey. When reflecting on the prototype, most respondents (75.5%) reported that they would wear the device always or most of the time. Respondents indicated discreetness and comfort as important factors that increased their chance of uptake. Respondents suggested that people experiencing homelessness and those with low tolerance for opioids would be in greatest need of the device. Conclusions The majority of people sampled with a history of opioid use in an urban setting were interested in having access to a device capable of detecting and reversing an opioid overdose. Participants emphasized privacy and comfort as the most important factors influencing their willingness to use such a device. Trial registration NCT04530591.

The coronavirus disease (COVID-19) pandemic has created significant stressors for the academic and scientific community, with unique challenges for early-career physician-scientists. The pandemic-related disruptions have significantly affected research productivity, access to mentoring, professional development and networking opportunities, funding, and personal wellness. This is especially true for pulmonary and critical care medicine faculty because of the burden of specialized clinical care responsibilities that the COVID-19 pandemic has demanded. Departmental, institutional, and national leadership should foster open dialogue to identify and mitigate these challenges to promote ongoing career development of early-career physician-scientists. Implementation of thoughtful interventions to address these challenges will provide essential support for junior faculty and help retain a generation of physician-scientists.

Background As medical infrastructures are strained by SARS-CoV-2, rapid and accurate screening tools are essential. In portions of the world, reverse transcription polymerase chain reaction (RT-PCR) testing remains slow and in limited supply, and computed tomography is expensive, inefficient, and involves exposure to ionizing radiation. Multiple studies evaluating the efficiency of lung point-of-care ultrasound (POCUS) have been published recently, but include relatively small cohorts and often focus on characteristics associated with severe illness rather than screening efficacy. This study utilizes a retrospective cohort to evaluate the test characteristics (sensitivity, specificity, likelihood ratios, predictive values) of lung POCUS in the diagnosis of SARS-CoV-2, and to determine lung score cutoffs that maximize performance for use as a screening tool. Results Lung POCUS examinations had sensitivity 86%, specificity 71.6%, NPV 81.7%, and PPV 77.7%. The Lung Ultrasound Score had an area under the curve of 0.84 (95% CI 0.78, 0.90). When including only complete examinations visualizing 12 lung fields, lung POCUS had sensitivity 90.9% and specificity 75.6%, with NPV 87.2% and PPV 82.0% and an area under the curve of 0.89 (95% CI 0.83, 0.96). Lung POCUS was less accurate in patients with a history of interstitial lung disease, severe emphysema, and heart failure. Conclusions When applied in the appropriate patient population, lung POCUS is an inexpensive and reliable tool for rapid screening and diagnosis of SARS-CoV-2 in symptomatic patients with influenza-like illness. Adoption of lung POCUS screening for SARS-CoV-2 may identify patients who do not require additional testing and reduce the need for RT-PCR testing in resource-limited environments and during surge periods.

After acute ischemic stroke, the cerebral vasculature is known to become more permeable to circulating leukocytes (WBC). Several laboratories attempted to use this for co-opting WBC do deliver into the central nervous system drugs and nanoparticle (NP) loaded into WBC ex vivo or in the peritoneal cavity. In theory, intravascular loading WBC may provide an interesting alternative. We hypothesize: i) direct in vivo targeting of WBC accessible to NP in the bloodstream (mainly pulmonary intravascular monocytes and marginated neutrophils in lungs), followed by carrier WBC migration to the brain will allow NP delivery to the brain and, ii) that targeted NP against WBC would be a relevant in treatment of acute brain inflammation. In fact, intravenous injection of ICAM-targeted NP 2h after the injection of tumor necrosis factor (TNF) in the brain initially showed a low uptake of the carrier in the brain that increased with time, as shown by radiotracing (5 times increase) and intravital microscopy of the brain. However, ICAM targeted NP were rapidly accumulated in the lungs and declined with time. Complete blood counts and flow cytometry revealed: i) an increase in circulating WBC counts following injury, ii) >60% of the ICAM-targeted NP were uptaken by WBC in the lungs, iii) ICAM targeted NP were almost exclusively in WBC in the brain (>98%; panel A shows the cellular distribution). Finally, we observed that the anti-inflammatory drug dexamethasone reduces brain edema only when encapsulated in ICAM-targeted nanoparticles (panel B). In conclusion, ICAM targeted NP: i) can be taken up by WBC, ii) migrate to the inflamed brain and iii) can reduce brain edema when encapsulating dexamethasone.

Targeted drug delivery is an attractive strategy for treatment of life-threatening inflammatory brain pathologies such as ischemic stroke. In these conditions, adhesion molecule expression (e.g. vascular cellular adhesion molecule-1, VCAM) is upregulated on endothelium. Hence, VCAM represents a relevant target for selective drug delivery. We have utilized αVCAM monoclonal antibodies to target therapeutic proteins and nanocarriers (liposomes and lipid nanoparticles, LNPs) to the pathologically-altered vasculature.To assess tissue biodistribution and therapeutic effects of VCAM-targeted agents, we used 2 mouse models: 1) acute inflammation induced by intra-striatal injection of tumor necrosis factor-α (TNF), and 2) ischemic stroke induced by transient middle cerebral artery occlusion (tMCAO). Biodistribution was assayed by measuring radioactivity in blood and organs 30 minutes after injection. Efficacy was determined by tracing radiolabeled albumin extravasation to assess edema.The results showed that VCAM targeting was increased by TNF injection, and that targeting to VCAM enhanced the cerebral accumulation of αVCAM conjugated thrombomodulin (TM) and nanocarriers by orders of magnitude (Fig A). It is noteworthy that αVCAM-TM and free αVCAM antibody had similar levels of brain uptake. Our data also demonstrated the protective effect of αVCAM-liposome loaded with dexamethasone on brain edema (Fig B), indicating the therapeutic potential of VCAM-targeting drug delivery strategies. Further, the results in tMCAO model recapitulated our findings in the TNF model that targeting to VCAM significantly improves delivery to the ischemic brain (Fig C). In summary, we have shown that targeting VCAM permits delivery of a diverse array of therapeutics to the inflamed vasculature in conditions such as ischemic stroke. Future work will focus on evaluating the therapeutic properties of VCAM-targeted drug delivery strategies.

Sport specialisation is becoming increasingly common among youth and adolescent athletes in the USA and many have raised concern about this trend. Although research on sport specialisation has grown significantly, numerous pressing questions remain pertaining to short-term and long-term effects of specialisation on the health and well-being of youth, including the increased risk of overuse injury and burnout. Many current elite athletes did not specialise at an early age. Methodological and study design limitations impact the quality of current literature, and researchers need to prioritise pressing research questions to promote safe and healthy youth sport participation. The American Medical Society for Sports Medicine hosted a Youth Early Sport Specialization Summit in April 2019 with the goal of synthesising and reviewing current scientific knowledge and developing a research agenda to guide future research in the field based on the identified gaps in knowledge. This statement provides a broad summary of the existing literature, gaps and limitations in current evidence and identifies key research priorities to help guide researchers conducting research on youth sport specialisation. Our goals are to help improve the quality and relevance of research on youth sport specialisation and to ultimately assure that opportunities for healthy and safe sport participation continue for all youth.

Acute lung inflammation has severe morbidity, as seen in COVID-19 patients. Lung inflammation is accompanied or led by massive accumulation of neutrophils in pulmonary capillaries (“margination”). We sought to identify nanostructural properties that predispose nanoparticles to accumulate in pulmonary marginated neutrophils, and therefore to target severely inflamed lungs. We designed a library of nanoparticles and conducted an in vivo screen of biodistributions in naive mice and mice treated with lipopolysaccharides. We found that supramolecular organization of protein in nanoparticles predicts uptake in inflamed lungs. Specifically, nanoparticles with agglutinated protein (NAPs) efficiently home to pulmonary neutrophils, while protein nanoparticles with symmetric structure (e.g. viral capsids) are ignored by pulmonary neutrophils. We validated this finding by engineering protein-conjugated liposomes that recapitulate NAP targeting to neutrophils in inflamed lungs. We show that NAPs can diagnose acute lung injury in SPECT imaging and that NAP-like liposomes can mitigate neutrophil extravasation and pulmonary edema arising in lung inflammation. Finally, we demonstrate that ischemic ex vivo human lungs selectively take up NAPs, illustrating translational potential. This work demonstrates that structure-dependent interactions with neutrophils can dramatically alter the biodistribution of nanoparticles, and NAPs have significant potential in detecting and treating respiratory conditions arising from injury or infections.

BACKGROUND:Extraglottic airway device (EGA) failure can be associated with severe complications and adverse patient outcomes. Prior research has identified patient- and procedure-related predictors of EGA failure. In this retrospective study, we assessed the incidence of perioperative EGA failure at

Humoral and cellular host defense mechanisms including diverse phagocytes, leukocytes, and immune cells have evolved over millions of years to protect the body from microbes and other external and internal threats. These policing forces recognize engineered sub-micron drug delivery systems (DDS) as such a threat, and react accordingly. This leads to impediment of the therapeutic action, extensively studied and discussed in the literature. Here, we focus on side effects of DDS interactions with host defenses. We argue that for nanomedicine to reach its clinical potential, the field must redouble its efforts in understanding the interaction between drug delivery systems and the host defenses, so that we can engineer safer interventions with the greatest potential for clinical success.

The ubiquity and potency of antibiotics may give the false impression that infection is a solved problem. Unfortunately, even bacterial infections, the target of antibiotics, remain a major cause of illness and death. Several major unmet needs persist: biofilms, such as those on implanted hardware, largely resist antibiotics; the inflammatory host response to infection often produces more damage than the infection itself; and systemic antibiotics often decimate the gut microbiome, which can predispose to additional infections and even predispose to non-infectious diseases. Additionally, there is an increasing threat from multi-drug resistant microorganisms, though market forces may continue to inhibit innovation in this realm. These numerous unmet infection-related needs provide attractive goals for innovation of targeted drug delivery technologies, especially those of nanomedicine. Here we review several of those innovations in pre-clinical development, the two such therapies which have made it to clinical use, and the opportunities for further technology development for treating infections.

The pulmonary vasculature plays an important role in many lung pathologies, such as pulmonary arterial hypertension, primary graft dysfunction of lung transplant, and acute respiratory distress syndrome. Therapy for these diseases is quite limited, largely due to dose-limiting side effects of numerous drugs that have been trialed or approved. High doses of drugs targeting the pulmonary vasculature are needed due to the lack of specific affinity of therapeutic compounds to the vasculature. To overcome this problem, the field of targeted drug delivery aims to target drugs to the pulmonary endothelial cells, especially those in pathological regions. The field uses a variety of drug delivery systems (DDSs), ranging from nano-scale drug carriers, such as liposomes, to methods of conjugating drugs to affinity moieites, such as antibodies. These DDSs can deliver small molecule drugs, protein therapeutics, and imaging agents. Here we review targeted drug delivery to the pulmonary endothelium for the treatment of pulmonary diseases. Cautionary notes are made of the risk–benefit ratio and safety—parameters one should keep in mind when developing a translational therapeutic.

Die Datenlage zur Wirksamkeit der therapeutischen Hypothermie in verschiedenen Patientengruppen ist heterogen. Wahrend der Nutzen in manchen Kollektiven belegt ist, beruhen Empfehlungen zum Einsatz der Hypothermietherapie in anderen Gruppen auf weniger robusten Daten und Analogieschlussen. Der vorliegende Beitrag gibt eine Ubersicht uber den aktuellen Kenntnisstand des Temperaturmanagements in allen Altersgruppen und empfiehlt bei Kindern jenseits der Neonatalperiode nach einem Atem-Kreislauf-Stillstand oder schwerem Schadel-Hirn-Trauma ein aktiv kontrolliertes Temperaturmanagement, mit dem primaren Ziel der strikten Normothermie (36,0–36,5 °C Korperkerntemperatur) fur 72 Stunden.

Kindernotfalle sind im Bereich der praklinischen Notfallmedizin seltene Ereignisse und u. a. deshalb fur Notarzte und Rettungsdienstkrafte oft mit Stress und Unsicherheit verbunden. Es existiert eine Vielzahl verschiedener kognitiver Hilfsmittel (Bucher, Apps, Lineale, gewichtsadaptierte Taschensysteme etc.), um im padiatrischen Notfall die adaquate Versorgung sicherzustellen. Insbesondere die richtige Grosenauswahl der Ausrustung und die Dosierung der Notfallmedikamente sind bei Kindern individuell sehr unterschiedlich und abhangig von Kenngrosen wie der Korperlange und dem Korpergewicht. Kognitive Hilfsmittel beinhalten deshalb oftmals die Moglichkeit der Langenmessung, von der wiederum auf das Gewicht als Leitwert zur Dosisberechnung von Medikamenten ruckgeschlossen werden kann. Zwar konnen diese Hilfsmittel die Fehldosierung und -behandlung von Kindern im Notfall verhindern helfen, ihr unkritischer und nicht im Vorfeld trainierter Einsatz birgt aber auch die Gefahr der falschen Anwendung. Diese Empfehlung bietet einen Uberblick uber die allgemeinen Anforderungen und Probleme verschiedener Arten kognitiver Hilfsmittel und soll dazu beitragen, die Rahmenbedingungen und die rationale Basis fur den Einsatz und die Weiterentwicklung kognitiver Hilfsmittel in der Notfallmedizin zu verbessern.

After dozens of clinical trials, there are still no Food and Drug Administration–approved drugs that improve mortality in acute respiratory distress syndrome (ARDS). These poor results may be caused in part by three unique pharmacological challenges presented by ARDS: (1) Patients with ARDS are fragile because of concomitant multiple organ dysfunction, so they do not tolerate off-target side effects of drugs; (2) inhaled drug delivery is impeded by the column of proteinaceous fluid covering the injured alveoli; and (3) ARDS is heterogeneous in its underlying pathophysiology, so targeting one pathway is unlikely to improve most patients. To address these three pharmacological problems, I present the development of pulmonary endothelium–targeted liposomes (PELs). PELs are approximately 100-nm drug carriers coated with antibodies that bind to the pulmonary capillary endothelium. In model organisms, intravenously injected PELs strongly concentrate drugs in alveoli, even in animal models displaying severe, spatially heterogeneous pathology similar to severe ARDS. By concentrating drugs in inflamed alveoli, PELs solve pharmacological challenge (1) above. By being obligate intravenous medications, they solve challenge (2). Finally, because PELs can be loaded with at least three drugs, they can solve challenge (3) with combination drug therapy. My colleagues and I are currently testing PELs loaded with numerous candidate drugs in mouse models of ARDS, and we are testing drug distribution in live pigs and ex vivo human lungs. We aim to use such preclinical validation to move PELs into a partnership with industry, and then to patients.

Drug targeting to inflammatory brain pathologies such as stroke and traumatic brain injury remains an elusive goal. Using a mouse model of acute brain inflammation induced by local tumor necrosis factor alpha (TNFα), we found that uptake of intravenously injected antibody to vascular cell adhesion molecule 1 (anti-VCAM) in the inflamed brain is >10-fold greater than antibodies to transferrin receptor-1 and intercellular adhesion molecule 1 (TfR-1 and ICAM-1). Furthermore, uptake of anti-VCAM/liposomes exceeded that of anti-TfR and anti-ICAM counterparts by ∼27- and ∼8-fold, respectively, achieving brain/blood ratio >300-fold higher than that of immunoglobulin G/liposomes. Single-photon emission computed tomography imaging affirmed specific anti-VCAM/liposome targeting to inflamed brain in mice. Intravital microscopy via cranial window and flow cytometry showed that in the inflamed brain anti-VCAM/liposomes bind to endothelium, not to leukocytes. Anti-VCAM/LNP selectively accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenger RNA (mRNA). Anti-VCAM/LNP-mRNA mediated expression of thrombomodulin (a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage) and alleviated TNFα-induced brain edema. Thus VCAM-directed nanocarriers provide a platform for cerebrovascular targeting to inflamed brain, with the goal of normalizing the integrity of the blood-brain barrier, thus benefiting numerous brain pathologies.

The bloodstream is the main transporting pathway for drug delivery systems (DDS) from the site of administration to the intended site of action. In many cases, components of the vascular system represent therapeutic targets. Endothelial cells, which line the luminal surface of the vasculature, play a tripartite role of the key target, barrier, or victim of nanomedicines in the bloodstream. Circulating DDS may accumulate in the vascular areas of interest and in off-target areas via mechanisms bypassing specific molecular recognition, but using ligands of specific vascular determinant molecules enables a degree of precision, efficacy, and specificity of delivery unattainable by non-affinity DDS. Three decades of research efforts have focused on specific vascular targeting, which have yielded a multitude of DDS, many of which are currently undergoing a translational phase of development for biomedical applications, including interventions in the cardiovascular, pulmonary, and central nervous systems, regulation of endothelial functions, host defense, and permeation of vascular barriers. We discuss the design of endothelial-targeted nanocarriers, factors underlying their interactions with cells and tissues, and describe examples of their investigational use in models of acute vascular inflammation with an eye on translational challenges., Graphical abstract Unlabelled Image

Objectives The aim of this report is to describe the lung biopsy findings in vaping-associated pulmonary illness. Methods Lung biopsies from eight patients with vaping-associated pulmonary illness were reviewed. Results The biopsies were from eight men (aged 19-61 years) with respiratory symptoms following e-cigarette use (vaping). Workup for infection was negative in all cases, and there was no evidence for other etiologies. Imaging showed diffuse bilateral ground-glass opacities in all patients. Most recovered with corticosteroid therapy, while one died. Lung biopsies (seven transbronchial, one surgical) showed acute lung injury, including organizing pneumonia and/or diffuse alveolar damage. Common features were fibroblast plugs, hyaline membranes, fibrinous exudates, type 2 pneumocyte hyperplasia, and interstitial organization. Some cases featured a sparse interstitial chronic inflammatory infiltrate. Although macrophages were present within the airspaces in all cases, this feature was not prominent, and findings typical of exogenous lipoid pneumonia were absent. Conclusions The histopathology of acute pulmonary illness related to e-cigarette use (vaping) is characterized by acute lung injury patterns, supporting the contention that vaping can cause severe lung damage.

Fire risk mapping – mapping the probability of fire occurrence and spread – is essential for pre-fire management as well as for efficient firefighting efforts. Most fire risk maps are generated using static information on variables such as topography, vegetation density, and fuel instantaneous wetness. Satellites are often used to provide such information. However, long-term vegetation dynamics and the cumulative dryness status of the woody vegetation, which may affect fire occurrence and spread, are rarely considered in fire risk mapping. Here, we investigate the impact of two satellite-derived metrics that represent long-term vegetation status and dynamics on fire risk mapping – the long-term mean normalized difference vegetation index (NDVI) of the woody vegetation (NDVIW) and its trend (NDVIT). NDVIW represents the mean woody density at the grid cell, while NDVIT is the 5-year trend of the woody NDVI representing the long-term dryness status of the vegetation. To produce these metrics, we decompose time-series of satellite-derived NDVI following a method adjusted for Mediterranean woodlands and forests. We tested whether these metrics improve fire risk mapping using three machine learning (ML) algorithms (Logistic Regression, Random Forest, and XGBoost). We chose the 2007 wildfires in Greece for the analysis. Our results indicate that XGBoost, which accounts for variable interactions and non-linear effects, was the ML model that produced the best results. NDVIW improved the model performance, while NDVIT was significant only when NDVIW was high. This NDVIW–NDVIT interaction means that the long-term dryness effect is meaningful only in places of dense woody vegetation. The proposed method can produce more accurate fire risk maps than conventional methods and can supply important dynamic information that may be used in fire behavior models.

4618 Background: APACT was a phase III trial of adjuvant nab-paclitaxel + gemcitabine ( nab-P + Gem) vs Gem alone in patients with resected pancreatic cancer (PC) and the first adjuvant PC trial to use independently assessed DFS as the primary endpoint (DFS by investigator review was a prespecified sensitivity analysis). We examined concordance between independent and investigator DFS review. Methods: For the independent assessment, reviewers determined recurrence by computed tomography or magnetic resonance imaging but were blinded to treatment and clinical data. Investigator-assessed DFS was based on all available data. Concordance was summarized by κ statistics. Patients who did not have recurrence or were alive were censored at the last tumor assessment date with disease-free status or the randomization date if the last tumor assessment with disease-free status was missing. Patients who received new anticancer therapy or cancer-related surgery prior to recurrence or death were censored at the date of last tumor assessment with disease-free status prior to the start of new anticancer therapy or cancer-related surgery or the randomization date if the last tumor assessment date with disease-free status prior to the start of subsequent new anticancer therapy or cancer-related surgery was missing. All censoring rules were the same for analysis of DFS by independent and investigator review. Results: Median DFS by independent review was 19.4 ( nab-P + Gem) vs 18.8 (Gem) months (hazard ratio [HR] 0.88; 95% CI, 0.73 - 1.06; P = 0.18); median investigator-assessed DFS was 16.6 ( nab-P + Gem) vs 13.7 (Gem) months (HR 0.82; 95% CI, 0.69 - 0.97; nominal P = 0.017). Moderate concordance was found between independent- and investigator-assessed DFS (Table); similar results were observed in the nab-P + Gem (concordance, 78%; κ coefficient, 0.56) and Gem alone (concordance, 76%; κ coefficient, 0.53) arms. Conclusions: The results reflect the complexities of defining the recurrence timepoint accurately and suggest that radiological review in the absence of clinical context is suboptimal for recurrence detection in resected PC. These findings may inform future clinical trial design. Registration: EudraCT (2013-003398-91); ClinicalTrials.gov (NCT01964430). Clinical trial information: NCT01964430 . [Table: see text]

Red blood cells (RBC) have great potential as drug delivery systems, capable of producing unprecedented changes in pharmacokinetics, pharmacodynamics, and immunogenicity. Despite this great potential and nearly 50 years of research, it is only recently that RBC-mediated drug delivery has begun to move out of the academic lab and into industrial drug development. RBC loading with drugs can be performed in several ways—either via encapsulation within the RBC or surface coupling, and either ex vivo or in vivo—depending on the intended application. In this review, we briefly summarize currently used technologies for RBC loading/coupling with an eye on how pharmacokinetics is impacted. Additionally, we provide a detailed description of key ADME (absorption, distribution, metabolism, elimination) changes that would be expected for RBC-associated drugs and address unique features of RBC pharmacokinetics. As thorough understanding of pharmacokinetics is critical in successful translation to the clinic, we expect that this review will provide a jumping off point for further investigations into this area.

American football remains one of the most popular sports for young athletes. The injuries sustained during football, especially those to the head and neck, have been a topic of intense interest recently in both the public media and medical literature. The recognition of these injuries and the potential for long-term sequelae have led some physicians to call for a reduction in the number of contact practices, a postponement of tackling until a certain age, and even a ban on high school football. This statement reviews the literature regarding injuries in football, particularly those of the head and neck, the relationship between tackling and football-related injuries, and the potential effects of limiting or delaying tackling on injury risk.

Optogenetics allows rapid, temporally specific control of neuronal activity via targeted expression and activation of light-sensitive proteins. Implementation typically requires remote light sources and fiber-optic delivery schemes that impose significant physical constraints on natural behaviors. In this report we bypass these limitations using novel technologies that combine thin, mechanically soft neural interfaces with fully implantable, stretchable wireless radio power and control systems. The resulting devices achieve optogenetic modulation of the spinal cord and peripheral nervous system. This is demonstrated with two form factors; stretchable film appliques that interface directly with peripheral nerves, and flexible filaments that insert into the narrow confines of the spinal epidural space. These soft, thin devices are minimally invasive, and histological tests suggest they can be used in chronic studies. We demonstrate the power of this technology by modulating peripheral and spinal pain circuitry, providing evidence for the potential widespread use of these devices in research and future clinical applications of optogenetics outside the brain.

This article investigates the effect of the Boston Marathon Bombing on city residents— how the tragic incident changed, or did not change, how Bostonians live in and feel about their community and neighborhoods. Unlike prior research that began weeks or months after a terrorist attack and used retrospective reports, this study spans the focal event. An address-based sample of residents from three neighborhoods, distinct in racial and economic makeup was surveyed by mail using a three-contact protocol. About two-thirds of respondents answered a survey of neighborhood sentiments, and health and well-being in the days before the bombing (N = 581) and slightly over a third answered the survey after the bombing (N = 313). Assessments of safety, city and neighborhood satisfaction and solidarity, mental health, and other key measures vary greatly between the three neighborhoods, which are diverse in racial and economic composition, but also vary in proximity to the bomb site. Net of neighborhood differences, the bombing had a strong negative effect on neighborhood cohesion and reduced use of public transit. Strong interactions are also found between timing of survey completion (pre and post bombing) and neighborhood for assessments of neighborhood solidarity.

Die sekundare klinische Zustandsverschlechterung eines Neugeborenen in der fruhen Postnatalzeit kann mannigfaltige Ursachen haben, u. a. Sepsis, Herzfehler und Stoffwechselerkrankungen. Die klinische Symptomatik ist unspezifisch und haufig fulminant. Vor allem aber kann sie einen lebensbedrohlichen Notfall darstellen, dessen fruhzeitige Erkennung von elementarer Bedeutung ist. Diagnostik und Therapie mussen parallel ohne Zeitverzug erfolgen. Um dies zu gewahrleisten, sind regelmasige Schulungen aller an der Versorgung von Neugeborenen beteiligten Berufsgruppen unabdingbar.

Detection of external irritants by head nociceptor neurons has deep evolutionary roots. Irritant-induced aversive behavior is a popular pain model in laboratory animals. It is used widely in the formalin model, where formaldehyde is injected into the rodent paw, eliciting quantifiable nocifensive behavior that has a direct, tissue-injury-evoked phase, and a subsequent tonic phase caused by neural maladaptation. The formalin model has elucidated many antipain compounds and pain-modulating signaling pathways. We have adopted this model to trigeminally innervated territories in mice. In addition, we examined the involvement of TRPV4 channels in formalin-evoked trigeminal pain behavior because TRPV4 is abundantly expressed in trigeminal ganglion (TG) sensory neurons, and because we have recently defined TRPV4’s role in response to airborne irritants and in a model for temporomandibular joint pain. We found TRPV4 to be important for trigeminal nocifensive behavior evoked by formalin whisker pad injections. This conclusion is supported by studies with Trpv4−/− mice and TRPV4-specific antagonists. Our results imply TRPV4 in MEK-ERK activation in TG sensory neurons. Furthermore, cellular studies in primary TG neurons and in heterologous TRPV4-expressing cells suggest that TRPV4 can be activated directly by formalin to gate Ca2+. Using TRPA1-blocker and Trpa1−/− mice, we found that both TRP channels co-contribute to the formalin trigeminal pain response. These results imply TRPV4 as an important signaling molecule in irritation-evoked trigeminal pain. TRPV4-antagonistic therapies can therefore be envisioned as novel analgesics, possibly for specific targeting of trigeminal pain disorders, such as migraine, headaches, temporomandibular joint, facial, and dental pain, and irritation of trigeminally innervated surface epithelia.

The number of anterior cruciate ligament (ACL) injuries reported in athletes younger than 18 years has increased over the past 2 decades. Reasons for the increasing ACL injury rate include the growing number of children and adolescents participating in organized sports, intensive sports training at an earlier age, and greater rate of diagnosis because of increased awareness and greater use of advanced medical imaging. ACL injury rates are low in young children and increase sharply during puberty, especially for girls, who have higher rates of noncontact ACL injuries than boys do in similar sports. Intrinsic risk factors for ACL injury include higher BMI, subtalar joint overpronation, generalized ligamentous laxity, and decreased neuromuscular control of knee motion. ACL injuries often require surgery and/or many months of rehabilitation and substantial time lost from school and sports participation. Unfortunately, regardless of treatment, athletes with ACL injuries are up to 10 times more likely to develop degenerative arthritis of the knee. Safe and effective surgical techniques for children and adolescents continue to evolve. Neuromuscular training can reduce risk of ACL injury in adolescent girls. This report outlines the current state of knowledge on epidemiology, diagnosis, treatment, and prevention of ACL injuries in children and adolescents.

Many lung diseases, such as acute respiratory distress syndrome (ARDS), display significant regional heterogeneity, with patches of severely injured tissue adjacent to apparently healthy tissue. Current mouse models that aim to mimic ARDS generally produce diffuse injuries that cannot reproducibly generate ARDS’s regional heterogeneity. This deficiency prevents the evaluation of how well therapeutic agents reach the most injured regions, and precludes many regenerative medicine studies, since it is not possible to know which apparently healing regions suffered severe injury initially. Finally, these diffuse injury models must be mild to allow for survival, as their diffuse nature does not allow for residual healthy lung to keep an animal alive long enough for many drug and regenerative medicine studies. To solve all of these deficiencies of current animal models, we have created a simple and reproducible technique to selectively induce lung injury in specific areas of the lung. Our technique, catheter-in-catheter selective lung injury (CICSLI), involves guiding an inner catheter to a particular area of the lung and delivering an injurious agent mixed with nanoparticles (fluorescently and/or radioactively labeled) that can be used to track the location and extent of where the initial injury was, days later. Further, we demonstrate that CICSLI can produce a more severe injury than diffuse models, yet has much higher survival since CICSLI intentionally leaves undamaged lung regions. Collectively, these attributes of CICSLI will allow better study of how drugs act within heterogeneous lung pathologies and how regeneration occurs in severely damaged lung tissue, thereby aiding the development of new therapies for ARDS and other lung diseases.

Background Youth sport participation offers many benefits including the development of self-esteem, peer socialisation and general fitness. However, an emphasis on competitive success, often driven by goals of elite-level travel team selection, collegiate scholarships, Olympic and National team membership and even professional contracts, has seemingly become widespread. This has resulted in an increased pressure to begin high-intensity training at young ages. Such an excessive focus on early intensive training and competition at young ages rather than skill development can lead to overuse injury and burnout. ### Purpose To provide a systematic, evidenced-based review that will (1) assist clinicians in recognising young athletes at risk for overuse injuries and burnout; (2)delineate the risk factors and injuries that are unique to the skeletally immature young athlete; (3) describe specific high-risk overuse injuries that present management challenges and/or can lead to long-term health consequences; (4) summarise the risk factors and symptoms associated with burnout in young athletes; (5)provide recommendations on overuse injury prevention. ### Methodology Medical Subject Headings (MeSHs) and text words were searched on 26 March 2012 from MEDLINE, CINAHL and PsycINFO. The search yielded 953 unique articles. Additional articles were found using cross-referencing. The process was repeated on 10 July 2013 to review any new articles since the original search. Screening by the authors yielded a total of 208 relevant sources that were used for this article. Recommendations were classified using the Strength of Recommendation Taxonomy (SORT) grading system. ### Definition of overuse injury Overuse injuries occur due to repetitive submaximal loading of the musculoskeletal system when rest is not adequate to allow for structural adaptation to take place. Injury can involve the muscle-tendon unit, bone, bursa, neurovascular structures and the physis. Overuse injuries unique to young athletes include apophyseal injuries and physeal stress injuries. ### Epidemiology It is estimated that 27 million US youth between 6 and 18 years of age participate in …

Wilms tumor is the most common renal mass in infancy with peak incidence between 3 and 4 years old. Actual cure rates are around 90%. Current COG recommendations for imaging follow-up after treatment still include abdomino-pelvic CT for the first 18 months in a regimen that totals at least eight follow-up CTs before changing to US examinations. That represents a meaningful radiation exposure in patients who are more susceptible to stochastic effects, due to their low age. Previous recent findings indicate that the pelvic segment can be safely excluded from routine follow-up CT examination, reducing radiation exposure and its risks, especially in regard of gonadal exposure with no loss of relevant oncologic information. There is currently no justification to sustain the recommendation of pelvic CT to follow up all Wilms tumor treated patients. In accordance with as low as reasonably achievable (ALARA) principle, this practice should not be routinely indicated.

Sports specialization is becoming the norm in youth sports for a variety of reasons. When sports specialization occurs too early, detrimental effects may occur, both physically and psychologically. If the timing is correct and sports specialization is performed under the correct conditions, the athlete may be successful in reaching specific goals. Young athletes who train intensively, whether specialized or not, can also be at risk of adverse effects on the mind and body. The purpose of this clinical report is to assist pediatricians in counseling their young athlete patients and their parents regarding sports specialization and intensive training. This report supports the American Academy of Pediatrics clinical report “Overuse Injuries, Overtraining, and Burnout in Child and Adolescent Athletes.”

After assessment of thermal sensitivity during development of a novel cold pain assay, one subject developed postinflammatory hyperpigmentation. Resultant epidermal darkening gradually faded without clinical intervention., Changes in cold temperature sensitivity are often associated with chronic pain conditions. Progress in understanding the neurobiological mechanism underlying these changes and resulting development of effective therapies has been slowed by the accessibility and affordability of devices used to measure thermal sensitivity in humans. To address this gap, we developed an inexpensive method to measure cold pain thresholds in healthy adult volunteers using dry ice and a thermode. However, early in preliminary testing, a subject presented with epidermal postinflammatory hyperpigmentation that lasted for >200 days. Although this response was unique among the small number of subjects in development of the assay, it raised questions as to the safety of the assay design.

More young children are participating in endurance running events such as full and half marathons, and the safety of these events for children has been heavily debated. There is a paucity of evidence on either side of the debate. However, overuse injuries, stress fractures, as well as the potential for psychologic burnout are legitimate concerns. Parents who are seeking advice from pediatricians about child participation in these endurance events should be made aware of these risks. Young children may participate in endurance running events under close supervision from health professionals, coaches, and parents, with full medical evaluation before initiation of training, throughout training, as well as 6 to 12 months post-race. Special attention should be made to the psychologic well-being of the child, with the participation in running being child-driven, not parent- or coach-driven, and emphasis on enjoyment and fitness, not competition. [ Pediatr Ann . 2016;45(3):e83–e86.]